He Miao, Bian Zhuan
State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Department of Pediatric Dentistry, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
PLoS One. 2016 Jul 26;11(7):e0159940. doi: 10.1371/journal.pone.0159940. eCollection 2016.
Grainyhead-like-3 (GRHL3) was recently identified as the second gene that, when mutated, can leads to Van der Woude syndrome, which is characterized by orofacial clefts (OFC) and lower lip pits. In addition, a missense variant (rs41268753) in GRHL3 confers risk for non-syndromic cleft palate cases of European ancestry. Together with interferon regulatory factor 6 (IRF6), GRHL3 may be associated with the risk of NSOFC which awaits for being verified across different ethnic populations.
The aim of this study was to investigate the possible relationship between common functional variants in GRHL3 and susceptibility to NSOFC, especially cleft palate cases, in a Han Chinese population, one of the ethnic groups with the highest birth prevalence of orofacial clefting.
Because the allele frequency for rs41268753 minor alleles was zero in our Chinese population, we selected functional single nucleotide polymorphisms (SNPs) spanning GRHL3 with minor allele frequencies (MAFs) > 5% in the Han Chinese population. Two SNPs which meet the above criteria were then genotyped in a case-control cohort comprising 1145 individuals using the TaqMan 5'-exonuclease allelic discrimination assay.
SNPs rs2486668 and rs545809 were used in this study. Overall genotype and allele distributions of both SNPs in general and stratified genotyping analyses revealed no statistically significant differences between cases and controls. Further logistic regression analyses using different genetic models failed to reveal any evidence that these markers influence risk to NSOFC.
The variant rs41268753 in GRHL3 increases the risk for cleft palate in European population, but our findings failed to detect the link between two GRHL3 SNPs (rs2486668 and rs545809) and risk to NSOFC in the Han Chinese cohort. Although the present study did not provide any evidence that common functional variants in GRHL3 may contribute to NSOFC etiology in this Chinese population, further studies with a larger sample size, additional SNPs, and a more diverse ethnic cohort are still warranted.
颗粒头样蛋白3（GRHL3）最近被确定为第二个发生突变时可导致范德伍迪综合征的基因，该综合征的特征为口面部裂隙（OFC）和下唇凹陷。此外，GRHL3中的一个错义变体（rs41268753）会增加欧洲血统非综合征性腭裂病例的患病风险。GRHL3与干扰素调节因子6（IRF6）共同作用，可能与非综合征性口面部裂隙（NSOFC）的风险相关，这一点有待在不同种族人群中进行验证。
本研究旨在调查GRHL3常见功能变体与中国汉族人群非综合征性口面部裂隙易感性（尤其是腭裂病例）之间的可能关系，中国汉族是口面部裂隙出生患病率最高的种族之一。
由于我们中国人群中rs41268753次要等位基因的频率为零，因此我们选择了在汉族人群中次要等位基因频率（MAF）>5%的跨越GRHL3的功能性单核苷酸多态性（SNP）。然后，使用TaqMan 5'-核酸外切酶等位基因鉴别分析，对一个包含1145名个体的病例对照队列中的两个符合上述标准的SNP进行基因分型。
本研究使用了SNP rs2486668和rs545809。在总体和分层基因分型分析中，这两个SNP的总体基因型和等位基因分布在病例组和对照组之间均未显示出统计学上的显著差异。使用不同遗传模型进行的进一步逻辑回归分析未能发现任何证据表明这些标记会影响非综合征性口面部裂隙的风险。
GRHL3中的变体rs41268753会增加欧洲人群患腭裂的风险，但我们的研究结果未能发现GRHL3的两个SNP（rs2486668和rs545809）与中国汉族队列中非综合征性口面部裂隙风险之间的联系。虽然本研究没有提供任何证据表明GRHL3中的常见功能变体可能导致中国人群中非综合征性口面部裂隙的病因，但仍需要进行更大样本量、更多SNP以及更多样化种族队列的进一步研究。
